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Inhibition of Autophagy via Lysosomal Impairment Enhances Cytotoxicity of Fullerenol under Starvation Condition
ACS Applied Bio Materials ( IF 4.7 ) Pub Date : 2020-01-21 , DOI: 10.1021/acsabm.9b01001
Liyun Yang 1, 2 , Siyu Hua 1 , Junpeng Fan 3 , Zhiqiang Zhou 1, 2 , Guanchao Wang 1 , Fenglei Jiang 1 , Zhixiong Xie 3 , Qi Xiao 2 , Yi Liu 1, 2
Affiliation  

Autophagy is well-known as a common cellular response to nanomaterials. As one of the most comprehensively studied carbon-based nanomaterials, fullerene and its derivatives have been reported to bring about autophagic features in various cell lines, but little is known about the role of fullerenol (C60(OH)44) on the modulation of autophagy in human gastric tumor cell line SGC-7901. Fullerenol treatment led to the accumulation of autophagosomes, as evidenced by the increased fluorescent intensity of monodansylcadaverine (MDC) staining cells, an elevated level of LC3 protein, and the observation of auotphagosomes in cytoplasm. Subsequent results of the p62 level demonstrated that the accumulation of autophagosomes resulted from the blockade of autophagic flux rather than the activation of autophagy. Fullerenol disrupted autophagic flux by impairing lysosomal function, including lysosome membrane permeabilization (LMP), alkaline of lysosomes, and reduced activity of capthesin B. Interestingly, fullerenol treatment was noncytotoxic under a nutrient-rich condition. When serum was deprived, cytotoxicity occurred in a concentration- and time-dependent manner, along with massive vacuoles in cytoplasm, a large amount of ROS generation, and finally cell death, which can be ascribed to the disruption of essential autophagy in cells. Taken together, understanding this autophagy–lysosome pathway will shed light on the potential anticancer application of fullerenol.

中文翻译:

通过溶酶体损伤抑制自噬增强饥饿条件下富勒烯醇的细胞毒性

自噬是众所周知的对纳米材料的常见细胞反应。作为研究最全面的碳基纳米材料之一,富勒烯及其衍生物已被报道在各种细胞系中引起自噬特性,但关于富勒烯醇(C 60 (OH) 44 )的作用知之甚少。) 对人胃肿瘤细胞系 SGC-7901 中自噬的调节。富勒烯醇处理导致自噬体的积累,这可以通过单丹磺酰尸胺 (MDC) 染色细胞的荧光强度增加、LC3 蛋白水平升高以及在细胞质中观察到自噬体来证明。p62水平的后续结果表明,自噬体的积累是由于自噬通量的阻断而不是自噬的激活。富勒烯醇通过损害溶酶体功能来破坏自噬通量,包括溶酶体膜通透性 (LMP)、溶酶体的碱性和降低的 capthesin B 活性。有趣的是,富勒烯醇处理在营养丰富的条件下是无细胞毒性的。当血清被剥夺时,细胞毒性以浓度和时间依赖性方式发生,伴随着细胞质中的大量空泡,大量活性氧的产生,最终导致细胞死亡,这可归因于细胞中必需的自噬的破坏。总之,了解这种自噬-溶酶体途径将有助于阐明富勒烯醇的潜在抗癌应用。
更新日期:2020-01-22
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